Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)

• DOI: 10.1172/jci200318062
• Publication Date: 2003-10-01T21:12:37Z
• Authors: D. Woodrow Benson; Dao W. Wang; Macaira Dyment; Timothy K. Knilans; Frank A. Fish; Margaret J. Strieper; Thomas H. Rhodes; Alfred L. George
• Keywords: Sick sinus syndrome; SSS*; Sinus bradycardia; Proband

Sick sinus syndrome (SSS) describes an arrhythmia phenotype attributed to node dysfunction and diagnosed by electrocardiographic demonstration of bradycardia or arrest. Although frequently associated with underlying heart disease seen most often in the elderly, SSS may occur fetus, infant, child without apparent cause. In this setting, is presumed be congenital. Based on prior associations disorders cardiac rhythm conduction, we screened α subunit sodium channel (SCN5A) as a candidate gene ten pediatric patients from seven families who were congenital during first decade life. Probands three kindreds exhibited compound heterozygosity for six distinct SCN5A alleles, including two mutations previously dominant excitability. Biophysical characterization mutants using heterologously expressed recombinant human channels demonstrate loss function significant impairments gating (inactivation) that predict reduced myocardial Our findings reveal molecular basis some forms define recessive disorder voltage-gated channel.